Background

Recent evidence shows that inducing ferroptosis may improve efficacy of tumor therapy. However, ferroptosis-related genes have been little studied in patients with breast cancer especially in the neoadjuvant setting. ACSL4 and GPX4 have been well established as the positive and negative regulator of ferroptosis, respectively. This study aimed to explore the predictive value of ACSL4 and GPX4 for patients with breast cancer administered neoadjuvant chemotherapy.

Methods

This study included patients treated with paclitaxel-cisplatin-based neoadjuvant chemotherapy. Immunohistochemistry staining of ACSL4 and GPX4 was carried out on the core needle biopsy specimens. Logistic regression was performed to explore the predictive biomarkers of pathological complete response (pCR). Survival analyses were examined by log-rank test and Cox proportional hazard regression.

Findings

A total of 199 patients were included for the analyses. Both ACSL4 expression and ACSL4/GPX4 combination status could serve as independent predictive factors for pCR. The interaction for pCR was observed between ACSL4 and clinical tumor stage. Besides, ACSL4 expression, GPX4 expression, and their combination status were independent prognostic factors for disease-free survival. Analyses of the Kaplan-Meier Plotter database suggested that higher ACSL4 expression is related to better overall survival, and higher GPX4 expression is related to better distant metastasis-free survival. Pathway analyses revealed that ACSL4 and GPX4 might function in crucial pathways including apoptosis, autophagy, cell adhesion, lipid metabolism, etc.

Interpretation

This study revealed the critical value of ACSL4 and GPX4 serving as novel predictive and prognostic biomarkers for patients with breast cancer receiving neoadjuvant chemotherapy. It might be a novel strategy to induce ferroptosis to promote chemosensitivity. Future studies are required to elucidate the potential mechanisms.

Funding

This work was supported by Shanghai Natural Science Foundation [grant number 19ZR1431100], Clinical Research Plan of Shanghai Hospital Development Center [grant numbers SHDC2020CR3003A, 16CR3065B, and 12016231], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Youth Medical Talents - Specialist Program [grant number 2018-15], Shanghai “Rising Stars of Medical Talent” Youth Development Program for Outstanding Youth Medical Talents [grant number 2018-16], Shanghai Collaborative Innovation Center for Translational Medicine [grant number TM201908], Multidisciplinary Cross Research Foundation of Shanghai Jiao Tong University [grant numbers YG2017QN49, ZH2018QNA42, and YG2019QNA28], Nurturing Fund of Renji Hospital [grant numbers PYMDT-002, PY2018-IIC-01, PY2018-III-15, and PYIII20-09], Science and Technology Commission of Shanghai Municipality [grant numbers 20DZ2201600 and 15JC1402700], and Shanghai Municipal Key Clinical Specialty.

中文翻译：

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铁死亡相关基因 ACSL4 和 GPX4 对新辅助化疗治疗乳腺癌的预测和预后影响

背景

最近的证据表明，诱导铁死亡可能会提高肿瘤治疗的疗效。然而，铁死亡相关基因在乳腺癌患者中的研究很少，尤其是在新辅助治疗中。ACSL4 和 GPX4 已分别被确定为铁死亡的正向和负向调节因子。本研究旨在探讨 ACSL4 和 GPX4 对乳腺癌新辅助化疗患者的预测价值。

方法

该研究包括接受紫杉醇-顺铂为基础的新辅助化疗的患者。对核心针活检标本进行 ACSL4 和 GPX4 的免疫组织化学染色。进行逻辑回归以探索病理完全缓解 (pCR) 的预测生物标志物。通过对数秩检验和 Cox 比例风险回归检查生存分析。

发现

共有 199 名患者被纳入分析。ACSL4 表达和 ACSL4/GPX4 组合状态均可作为 pCR 的独立预测因素。在 ACSL4 和临床肿瘤分期之间观察到 pCR 的相互作用。此外，ACSL4表达、GPX4表达及其组合状态是无病生存的独立预后因素。Kaplan-Meier Plotter 数据库的分析表明，较高的 ACSL4 表达与较好的总生存期有关，较高的 GPX4 表达与较好的无远处转移生存期有关。通路分析表明，ACSL4和GPX4可能在细胞凋亡、自噬、细胞粘附、脂质代谢等关键通路中发挥作用。

解释

这项研究揭示了 ACSL4 和 GPX4 作为新辅助化疗乳腺癌患者的新型预测和预后生物标志物的关键价值。这可能是一种诱导铁死亡以促进化学敏感性的新策略。未来的研究需要阐明潜在的机制。

资金

本工作得到上海市自然科学基金[19ZR1431100]、上海市医院发展中心临床研究计划[SHDC2020CR3003A、16CR3065B、12016231]、上海市“医学新星”青年医学人才发展计划-专科项目【2018-15】，上海市“医学新星”青年医学杰出人才培养计划【2018-16】，上海市转化医学协同创新中心【TM201908】，多学科交叉研究上海交通大学基金会[授权号YG2017QN49、ZH2018QNA42和YG2019QNA28]，仁济医院培育基金[授权号PYMDT-002、PY2018-IIC-01、PY2018-III-15和PYIII20-09]，上海市科委[批准号20DZ2201600和15JC1402700]，上海市临床重点专科。